Acquired Defences

Humoral Immunity

Exposure to a certain infectious disease creates a resistance to that disease. Specialised blood proteins called antibodies are produced which bind to the infectious agent or substance (antigen). This binding process destroys the antigen. B lymphocytes processed in the lymphatic tissue, outside the thymus gland, have specific antigen receptors called surface immunoglobulins. The reaction between the immunoglobulin and the antigen causes cell proliferation of the B cells into memory and plasma cells, which secrete large amounts of immunoglobulin molecules

Cell-Mediated Immunity

Lymphocytes, processed by the thymus (T lymphocytes) carry genetic information to bind with and destroy a multitude of antigens, yet recognise and remain inactive to antigens produced by the body’s own cells. T lymphocytes or T cells are classified into certain groups depending on their function, which may include enhancing the effects of other immune responses (T-helper cells) and suppressing or deactivating the response (T-regulator cells).

THE SYSTEMIC INFAMMATORY RESPONSE SYNDROME

The inflammatory process is self-contained by feedback mechanisms that increase and then limit inflammation (Steen 2009). However, the factor that has triggered the inflammation may be overwhelming or not contained, and/or the response itself may not be limited by feedback mechanisms. When this occurs systemic effects are noted which are described as the systemic inflammatory response syndrome (SIRS). This term has been used interchangeably over recent years with terms such as sepsis, septic shock and severe sepsis; there are, however, differences, which are illustrated in Table 15.1.

Table 15.1 Table of definitions

Adapted from Bone et al. (1992).

Patient Presentation

A major factor in SIRS is that any organ system in the body can be affected although some, such as the lungs, kidneys or clotting system are more vulnerable (Adam and Osborne, 2005), so presentation may differ. Levy et al. (2003) proposed the variables in Table 15.2 as possible signs of systemic inflammation in response to infection.

Table 15.2 Possible signs of systemic inflammation in response to infection

From Levy et al. (2003).

INR, international normalised ratio; PTT, partial thromboplastin time.

Levy et al. (2003) continue to suggest that SIRS can occur as result of a variety of insults, illustrated in Table 15.3. However, it is usually manifested by two or more of the following conditions:

• Temperature >38^oC

• Heart rate >90 beats/min
  
• Respiratory rate >20 breaths/min or hyperventilation with arterial partial pressure of carbon dioxide (PaO₂) 4.3 kPa
  
• White cell count >12 000 mm³ or <4000 mm³ or 10% immature neutrophils.

Table 15.3 Triggers for systemic inflammatory response syndrome (SIRS)

Levy et al. (2003).

The Pathophysiology of SIRS/Sepsis

The pathophysiological process of SIRS/sepsis is a result of inappropriate control of the normal responses to inflammation. The normal mechanisms of vasodilatation, leaky capillaries and clot formation are exaggerated (Robson et al. 2005) and may be continually reactivated. This cascade leads to organ dysfunction and failure.

The principal mechanisms of the cascade are as follows:

• Activation of the immune response and inflammatory mediators that activate the complement pathway, enhancing inflammation and phagocytosis. If large amounts of complement activation occur and appear systemically then actions become detrimental (Adam and Osborne 2005).
  
• The phagocytosis of the pathogenic organism by the white blood cells involves the release of certain proteases and oxygen free radicals which, if they enter the systemic circulation, cause further tissue damage.
  
• The coagulation pathway is triggered, by either the initial insult or endothelial damage caused predominantly by white blood cell activation. Disseminated intravascular coagulopathy (DIC) can occur if this reaction is not localised. Thrombi caused by DIC can interfere with blood flow to the tissues and organs, and together with hypotension and hypovolaemia can lead to organ failure (Robson et al. 2005).
  
• Platelet aggregation (clumping together) is triggered by endothelial damage and this compounds the DIC picture. Normally the body will attempt to break down any blood clots by fibrinolysis and will also release anti-inflammatory mediators to counterbalance the inflammatory mediators.

However, these counter-responses can be inhibited (Robson et al. 2005). The damaged endothelium continues to activate mediator release, which includes powerful vasodilatory substances such as bradykinin and endothelial-derived relaxing factor which, if are not localised, cause systemic vasodilatation with associated increased capillary permeability. This leads to hypotension, intravascular hypovolaemia and further organ hypoperfusion.

Sepsis is associated with systemic, mediator-induced alterations in oxygen utilisation, including increased oxygen demand, altered oxygen extraction and decreased myocardial contractility (Vincent 2008); this may be further influenced by maldistribution of blood flow and impaired oxygen diffusion.

MONITORING A PATIENT WITH SIRS/SEPSIS

Identifying patients with severe sepsis in primary care, emergency departments, wards or admission units is crucial to reducing mortality (Peel 2008). The Resuscitation Council (2006) recommend that clinical staff should follow the ABCDE approach when assessing (and treating) critically ill patients. This will help to ensure that critical illness is promptly identified and appropriately managed (Jevon 2010). The ABCDE framework illustrated throughout this text requires no modification in its application to the patient with SIRS/sepsis. However, its process is demonstrated below to identify key criteria that may lead to early recognition and prompt treatment

Airway

Should the degree of inflammatory response compromise respiratory function, as is common (Adam and Osborne 2005), mechanical ventilatory support may be indicated and an artificial airway will be required. This should be performed by senior anaesthetic staff with skilled assistance.

Breathing

There are many factors in SIRS that could lead towards respiratory compromise. These include:

• Chest infection as a primary cause of SIRS
  
• Ventilation–perfusion mismatch from maldistribution of blood volume and hypovolaemia
  
• Pulmonary oedema as a result of fluid shifts, changes in intravascular osmotic pressure and decreased myocardial contractility
  
• Mediator-induced alterations in oxygen use, including increased oxygen demand and altered oxygen extraction
  
• Increased respiratory drive due to metabolic acidosis (organ hypoperfusion and hyperlactataemia)
  
• Acute inflammatory changes in the lungs.

Breathing respiratory assessment should occur as outlined in Chapter 3. Basic assessment should include assessment of general colour, mental state and respiratory rate. Respiratory rhythm, regularity and chest expansion should all be noted (Docherty 2002); increases in respiratory rate may be driven by a metabolic acidosis caused by anaerobic metabolism. Work of breathing may be increased as demonstrated by tachypnoea and the use of accessory muscles. Abnormalities in gas exchange may be evident on arterial blood gas analysis; hypoxia and hypercapnia where present can alter mental state, so confusion/delirium may be present (Higgins and Guest 2008).

Systemic vasodilatation may cause the patient to look flushed, which could mask changes of respiratory failure such as cyanosis. The chest should be auscultated to identify any added sounds, such as wheeze or crepitations which may indicate oedema (Pryor and Prasad 2008).

The volume and characteristics of pulmonary secretions should be assessed (Adam and Osborne 2005); white/pink frothy secretions may indicate pulmonary oedema, whereas green/yellow offensive secretions may indicate an infective process in the chest. Adam and Osborne (2005) note that, in acute respiratory distress syndrome (ARDS), a common pulmonary presentation of respiratory failure associated with SIRS, secretions may well be loose and white becoming thicker and more profuse as the condition develops.

Pulse oximetry should be instituted, but this must complement basic assessment, not replace it. It must be remembered that pulse oximetry does not provide information on haemoglobin concentration, oxygen delivery to the tissues or ventilatory function, so a patient may have normal oxygen saturations yet still be hypoxic (Higgins 2005).

Arterial blood gas (ABG) analysis provides valuable information about a patient’s respiratory and metabolic function (Allen 2005) and is discussed in depth in Chapter 3. Hypoxia/hypercapnia may be present as discussed above, but it must be recalled that the presence of normal arterial blood oxygen content does not always correlate to oxygen delivery to the cells. A compensated or non-compensated metabolic acidosis may be present, which could indicate organ hypoperfusion, particularly when associated with a high lactate (a parameter now measured by most modern blood gas analysers. Lactate is elevated (above 4 mmol/l) in patients with poor tissue perfusion (Peel 2008).

Circulation

Factors that cause circulatory compromise in the patient with SIRS include:

• Distributive shock as a result of vasodilatation and hypovolaemia
  
• Increased risk of thromboembolus, in particular microemboli, causing microvascular obstruction and end-organ dysfunction
  
• Increased risk of haemorrhage from clotting factor and platelet consumption
  
• Decreased myocardial contractility in the presence of increased oxygen consumption (compensatory tachycardia) and decreased oxygen delivery (reduced diastolic time)
  
• Tissue hypoxia
  
• Hypo-/hyperthermia
  
• Electrolyte/acid–base balance.

Circulation assessment should occur as outlined in Chapter 5. Vasodilatation is likely to be present giving the patient a ‘flushed’ look; vasodilatation in the capillaries may be demonstrated by an increased capillary refill time (CRT) and warm digits.

Hypovolaemia is also likely to be present and a picture of dehydration may be noted including alteration of mental state. Compensatory mechanisms will include an increase in heart rate; pulse should be assessed for rate, volume and regularity; a bounding pulse, with an increased CRT will indicate a hyperdynamic state. A fast, weak volume pulse with decreased CRT could indicate hypovolaemia. Rhythm irregularity indicates arrhythmia. SIRS has been identified as a major trigger for tachyarrhythmias (Vincent 2009) so continual monitoring, and diagnostic 12-lead electrocardiography (ECG) will be required.

Blood pressure monitoring should be haemodynamic, using arterial cannulation with transduced pressures. Blood pressure may well appear normal reflecting compensation; diastolic hypotension may be an indication of reduced venous tone (vasodilatation). Systolic hypertension, particularly over a low diastolic value, may reflect the hyperdynamic state.

Activation of hormonal compensatory mechanisms, including the renin–angiotensin pathway, aldosterone and antidiuretic hormone, cause a decrease in urine output and reabsorption of sodium and water, so observation of urine output is an important indicator of hypoperfusion. A urine output of <0.5 ml/kg of body weight per hour can be used as an indicator of hypoperfusion.

Blood lactate measurement (and its response to treatment) may be a good indicator of organ perfusion (Fischer et al. 2006); however, this should be measured together with monitoring of end-organ function such as diuresis and alterations in mental state.

Disability

Brain dysfunction is often one of the first clinical symptoms in sepsis and may manifest as sepsis-associated delirium in up to 70% of patients (Pytel and Alexander 2009). The causes for neurological dysfunction in sepsis are poorly understood, but are thought to include decreased cerebral perfusion (Burkhart et al., 2010), micro-circulatory failure and changes in blood brain barrier permeability (Pytel and Alexander 2009). The sequela of other organ system failure may also carry some responsibility (Burkhart et al. 2010). Assessment should incorporate tools such as AVPU as outlined in Chapter 6 (Resuscitation Council UK 2006) plus pupillary size, and reaction to light. Blood sugar measurement should be performed at the earliest opportunity because imbalance may occur. Hyperglycaemia and insulin resistance as part of a physiological stress response are well documented (Ober 1999; Van Den Berghe 2008) Hypoglycaemia may also occur in non-diabetic and diabetic patients, particularly those with hepatic, renal and/or adrenocortical dysfunction. Capillary sampling in acutely ill patients may provide misleading results, particularly patients with circulatory failure, dehydration, alterations in oxygen tension and extremes of haematocrit, so venous sampling and laboratory analysis are recommended (Medicines and Healthcare products Regulatory Authority or MHRA 2005).

Exposure

Exposure should allow full examination of the patient with respect for dignity and the avoidance of heat loss (Resuscitation Council UK 2006). This will include a full clinical history, a review of notes/charts and any pertinent results. Examination should be comprehensive using a head-to-toe, or body systems, approach. The cause of the inflammatory response may not be known and the patient should be assessed for any possible septic foci.

The abdomen should be assessed and palpated and any guarding, tenderness or distension reported. Gastrointestinal losses should be noted for frequency and characteristics; gut motility tends to be reduced during critical illness, so nausea, vomiting or increased losses from drainage devices may be noted.

Wounds and wound drainage should be examined, with specimens taken for microbiological investigation as required. Further microbiological investigations, such as culture of blood, sputum or urine, will be required. In particular blood cultures should be taken at the earliest opportunity, the guidelines for which are discussed later in this text.

The patient should be examined for signs of fever, or hypothermia; a rise in temperature may indicate inflammation and/or fluctuations in basal metabolic rate. It will also provide a baseline against which to compare further readings.

The patients’ fluid balance should be assessed with consideration for insensible losses, which can be significantly increased in the septic patient. Insensible losses from increased respiratory work and excessive diaphoresis must not be overlooked. Oedema may well be noted as a result of intravascular–extravascular fluid shifting and reductions in intravascular osmotic pressure.

Ongoing Monitoring

Monitoring and managing the patient with SIRS are complex, requiring a multidisciplinary approach, the use of specialist support services and in most cases admission to a critical care unit for specialist skills and monitoring. This process is outlined from a systems perspective

Airway

The degree of respiratory compromise in SIRS is commonly severe enough to warrant artificial mechanical ventilation, which, in most cases requires airway intubation with an endotracheal tube. If this period of support is prolonged a temporary tracheostomy may be required.

The presence of any artificial airway increases the risks of pulmonary bacterial colonisation, and the likelihood of an HCAI (Newmarch 2006; Higgins 2009)

Respiratory System

As outlined above artificial mechanical ventilation may be required; this predisposes the patient to risks and associated complications, including physiological effects such as compromise to the cardiovascular system. There is also a well-documented association between mechanical ventilation and pneumonia (Henderson 1999; Selvaraj 2010). Monitoring the ventilated patient is beyond the scope of this chapter, but is discussed in Chapter 3.

The relationship between sepsis and ARDS is long established (Fein et al. 1983); the management of this process in itself is complex involving advanced supportive ventilator strategy and techniques. Pulse oximetry will guide therapy as will serial arterial blood gas analysis. Chest radiographs will be required, either as a diagnostic tool or to map inflammatory lung changes. The volume and characteristics of pulmonary secretions should be assessed (Adam and Osborne 2005) and microbiological investigations such as culture and identifying the sensitivity of any cultured organisms to antibacterial agents will be indicated. Some organisations recommend serial analysis, as a form of microbiological surveillance, whereas others perform culture and sensitivity when symptoms are evident. The incidence of ventilator-associated pneumonia (VAP) is again mentioned because patients may present with a septic focus in another organ system, but the ongoing management predisposes the patient to new risks that may further complicate the inflammatory response.

Cardiovascular Monitoring

Ongoing ECG monitoring will be required to detect changes in cardiac rhythm; serial diagnostic 12-lead recording may also be required if abnormality is suspected.

Blood pressure monitoring should be haemodynamic, using arterial cannulation with transduced pressures; this is discussed in depth in Chapter 5. Both systolic and diastolic pressures are measured, but frequently the mean arterial pressure (MAP) is used because it can approximate the perfusion of essential organs such as the kidneys (McGhee and Bridges 2002) Hence, MAP is central to goal-related therapy in clinical practice (Dünser et al. 2009).

Central venous pressure (CVP) should be monitored via a central venous catheter; again this is discussed in depth in Chapter 5. The practitioner is reminded that CVP is a reflection of four parameters – intrathoracic pressure, circulating volume, right-sided cardiac function and venous tone – and also to some degree blood viscosity; thus it must not be interpreted as a stand-alone value. Access to the central circulation allows measurement of venous oxygen saturations, which can reflect important pathophysiological changes in oxygen delivery and consumption (Shepherd and Pearse 2009); this can inform clinical practice and guide fluid resuscitation.

More advanced invasive monitoring of cardiac output and other derived values frequently occurs in the critical care unit. Although thermodilution measurement (using a pulmonary artery catheter) remains an established method of determining cardiac output, other techniques such as lithium dilution pulse contour analysis, Doppler ultrasonography offer a less invasive technique (Adam and Osborne 2005)

Serial ABG analysis will be required, not least to inform respiratory/ventilatory support and to provide an indication of tissue hypoperfusion which can be demonstrated by a metabolic acidosis and increased blood lactate

Microbiological Monitoring/Investigations

The clinical microbiology laboratory plays a fundamental role in the diagnosis of infection (Peterson et al. 2001), ongoing monitoring of the inflammatory response and the management of specific antimicrobial therapies. An appropriate microbiological test is one that is undertaken with the aim of influencing patient treatment (Storr et al. 2005).

In the patient with SIRS/sepsis identification of the causative microorganism is of paramount importance so that bactericidal/ virucidal agents can be delivered at the earliest opportunity.

The surviving sepsis campaign (Dellinger et al. 2008) recommends the following:

• Obtaining appropriate cultures (blood) before starting antibiotics provided that this does not significantly delay antimicrobial administration
  
• Obtaining two or more blood cultures (possibly using a vascular access device) but one should be percutaneous
  
• Obtaining a blood culture from each vascular access device that has been in place for more than 48 h
  
• The culture of other sites (sputum, urine, etc.) as clinically indicated.

Broad-spectrum antibiotics are indicated in sepsis and these should be administered as early as possible (Dellinger et al. 2008). Liaison with the microbiology team should occur to redirect (if required) therapy once any pathogenic organisms have been identified. Advice may also be required in managing the therapeutic levels of any particular drug therapy, e.g. vancomycin.

Biochemical and Haematological Monitoring

It is imperative to monitor biochemical markers to identify isolated or multiple organ failure associated with sepsis. Standardised biochemical and haematological profiles should be assessed frequently, as advised by laboratory staff. This will enable organ support to be initiated without delay.

Particular reference is made to indicators of renal function, coagulation profiles/platelet count, liver function tests and serum amylase. The inflammatory process can also be mapped by changes in white blood cell count, which may be raised or lowered A raised white cell count (>11 000/ml) may indicate bacterial infection if associated with a high neutrophil count and increased immature forms. C-reactive protein (CRP) may also be measured but, as with white blood cell count, this is a non-specific marker; it is, however, useful in mapping the inflammatory process. The half-life of CRP is short (5–7 h) and the decline in serum CRP concentration is a sensitive measure of the resolution of infection. Elevations in erythrocyte sedimentation rate and procalcitonin may also be observed. Other specific markers of the immunological response can be measured, including interleukins and specific mediators; these may help identify the specific cause/microorganism of infection.

Track-And-Trigger Systems

Physiological track and trigger should be used to monitor all adult patients in the acute hospital setting (National Institute for Health and Clinical Excellence or NICE 2007); these are discussed in depth in Chapter 1. Tools such as the modified early warning scoring system are ideal for monitoring the patient with SIRS/sepsis.

Other Investigations

A specific anatomical site of infection should be established as rapidly as possible and within first 6 h of presentation (Dellinger et al. 2008).

Diagnostic studies, e.g. ultrasonography, may identify a source of infection leading to early intervention.

SCENARIOS

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